Search

Current KRAS G12C (OFF) inhibitors that target inactive GDP-bound KRAS G12C cause responses in less than half of patients and these responses are not durable. A class of RAS G12C (ON) inhibitors that targets active GTP-bound KRAS G12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRAS G12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRAS G12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRAS G12C -dependent lung cancer., (© 2024. The Author(s).)

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Early changes in lung cancer care can affect survival. Given the decrease in diagnosis during lockdowns, we calculated their impact on survival using National Lung Cancer Audit data. Percentage survival and HRs for death were compared between 2019 and lockdown periods of 2020. Decreased survival was observed from the first national lockdown onwards and within 90 days of diagnosis. HRs were highest for people diagnosed at the end of 2020 at 1.26 (95% CI 1.20 to 1.32) for death within 90 days and 1.51 (95% CI 1.42 to 1.60) for death between 91 and 270 days. Further work is needed on measures to mitigate this impact., Competing Interests: Competing interests: DB reports grants from Cancer Research UK, personal fees from Roche, personal fees from Astra Zeneca, personal fees from MSD, personal fees from BMS, outside the submitted work. RH reports personal fees from Galapagos, outside the submitted work. NN is supported by an MRC Clinical Academic Research Partnership (MR/T02481X/1). NN has received fees or non-financial support from Amgen, Astra Zeneca, Bristol-Meyers Squibb, Lilly & Co, Merck Sharp and Dohme, Olympus, Oncimmune, OncLive, PeerVoice, Pfizer and Takeda, outside of the submitted work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Different treatment options are now possible both for surgical candidates and for those NSCLC patients deemed not suitable for surgery. Despite the treatments available, only a limited number of less advanced stages are potentially curable, with many patients suffering local recurrence or distant metastases. FDG-PET/CT is commonly used in many centers for post-treatment evaluation, follow-up, or surveillance; Nonetheless, there is no clear consensus regarding the indications in these cases. Based upon the results of a literature review and local expertise from a large lung cancer unit, we built clinical evidence-based recommendations for the use of FDG-PET/CT in response assessment. We found that in general this is not recommended earlier than 3 months from treatment; however, as described in detail the correct timing will also depend upon the type of treatment used. We also present a structured approach to assessing treatment changes when reporting FDG-PET/CT, using visual or quantitative approaches., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Risk-based screening for lung cancer is currently being considered in several countries; however, the optimal approach to determine eligibility remains unclear. Ensemble machine learning could support the development of highly parsimonious prediction models that maintain the performance of more complex models while maximising simplicity and generalisability, supporting the widespread adoption of personalised screening. In this work, we aimed to develop and validate ensemble machine learning models to determine eligibility for risk-based lung cancer screening., Methods and Findings: For model development, we used data from 216,714 ever-smokers recruited between 2006 and 2010 to the UK Biobank prospective cohort and 26,616 high-risk ever-smokers recruited between 2002 and 2004 to the control arm of the US National Lung Screening (NLST) randomised controlled trial. The NLST trial randomised high-risk smokers from 33 US centres with at least a 30 pack-year smoking history and fewer than 15 quit-years to annual CT or chest radiography screening for lung cancer. We externally validated our models among 49,593 participants in the chest radiography arm and all 80,659 ever-smoking participants in the US Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial. The PLCO trial, recruiting from 1993 to 2001, analysed the impact of chest radiography or no chest radiography for lung cancer screening. We primarily validated in the PLCO chest radiography arm such that we could benchmark against comparator models developed within the PLCO control arm. Models were developed to predict the risk of 2 outcomes within 5 years from baseline: diagnosis of lung cancer and death from lung cancer. We assessed model discrimination (area under the receiver operating curve, AUC), calibration (calibration curves and expected/observed ratio), overall performance (Brier scores), and net benefit with decision curve analysis. Models predicting lung cancer death (UCL-D) and incidence (UCL-I) using 3 variables-age, smoking duration, and pack-years-achieved or exceeded parity in discrimination, overall performance, and net benefit with comparators currently in use, despite requiring only one-quarter of the predictors. In external validation in the PLCO trial, UCL-D had an AUC of 0.803 (95% CI: 0.783, 0.824) and was well calibrated with an expected/observed (E/O) ratio of 1.05 (95% CI: 0.95, 1.19). UCL-I had an AUC of 0.787 (95% CI: 0.771, 0.802), an E/O ratio of 1.0 (95% CI: 0.92, 1.07). The sensitivity of UCL-D was 85.5% and UCL-I was 83.9%, at 5-year risk thresholds of 0.68% and 1.17%, respectively, 7.9% and 6.2% higher than the USPSTF-2021 criteria at the same specificity. The main limitation of this study is that the models have not been validated outside of UK and US cohorts., Conclusions: We present parsimonious ensemble machine learning models to predict the risk of lung cancer in ever-smokers, demonstrating a novel approach that could simplify the implementation of risk-based lung cancer screening in multiple settings., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: NN reports honoraria for non-promotional educational talks, conference support or advisory boards from Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Guardant Health, Janssen, Lilly, Merck Sharp & Dohme, Olympus, OncLive, PeerVoice, Pfizer, and Takeda. SMJ has received fees for advisory board membership in the last three years from Astra-Zeneca, Bard1 Lifescience, and Johnson and Johnson. He has received grant income from Owlstone and GRAIL Inc. He has received assistance with travel to an academic meeting from Cheisi. TC and SMJ are founders of, and own stock in, Mortimer Health., (Copyright: © 2023 Callender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria., Methods: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion., Results: Unanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76-0.92) and 0.86 (95% CI: 0.79-0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96-1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89-0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma., Conclusions: Our study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy., (Copyright © 2023. Published by Elsevier Inc.)

Background: The COVID-19 pandemic has caused significant disruption to health-care services and delivery worldwide. The impact of the pandemic and associated national lockdowns on lung cancer incidence in England have yet to be assessed., Research Question: What was the impact of the first year of the COVID-19 pandemic on the incidence and presentation of lung cancer in England?, Study Design and Methods: In this retrospective observational study, incidence rates for lung cancer were calculated from The National Lung Cancer Audit Rapid Cancer Registration Datasets for 2019 and 2020, using midyear population estimates from the Office of National Statistics as the denominators. Rates were compared using Poisson regression according to time points related to national lockdowns in 2020., Results: Sixty-four thousand four hundred fifty-seven patients received a diagnosis of lung cancer across 2019 (n = 33,088) and 2020 (n = 31,369). During the first national lockdown, a 26% reduction in lung cancer incidence was observed compared with the equivalent calendar period of 2019 (adjusted incidence rate ratio [IRR], 0.74; 95% CI, 0.71-0.78). This included a 23% reduction in non-small cell lung cancer (adjusted IRR, 0.77; 95% CI, 0.74-0.81) and a 45% reduction in small cell lung cancer (adjusted IRR, 0.55; 95% CI, 0.46-0.65) incidence. Thereafter, incidence rates almost recovered to baseline, without overcompensation (adjusted IRR, 0.96; 95% CI, 0.94-0.98)., Interpretation: The incidence rates of lung cancer in England fell significantly by 26% during the first national lockdown in 2020 and did not compensate later in the year., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Oncolytic virus therapies induce the direct killing of tumor cells and activation of conventional dendritic cells (cDC); however, cDC activation has not been optimized with current therapies. We evaluated the adenoviral delivery of engineered membrane-stable CD40L (MEM40) and IFNβ to locally activate cDCs in mouse tumor models. Combined tumor MEM40 and IFNβ expression induced the highest cDC activation coupled with increased lymph node migration, increased systemic antitumor CD8+ T-cell responses, and regression of established tumors in a cDC1-dependent manner. MEM40 + IFNβ combined with checkpoint inhibitors led to effective control of distant tumors and lung metastases. An oncolytic adenovirus (MEM-288) expressing MEM40 + IFNβ  in phase I clinical testing induced cancer cell loss concomitant with enhanced T-cell infiltration and increased systemic presence of tumor T-cell clonotypes in non-small cell lung cancer (NSCLC) patients. This approach to simultaneously target two major DC-activating pathways has the potential to significantly affect the solid tumor immunotherapy landscape., (©2023 American Association for Cancer Research.)

Metastatic disease is responsible for the majority of cancer-related deaths 1 . We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse., (© 2023. The Author(s).)

Lung cancer is the leading cause of cancer-associated mortality worldwide 1 . Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource., (© 2023. The Author(s).)

Introduction: In 2019, the National Institute for Health and Care Excellence (NICE) updated their recommendations with respect to brain imaging in the staging of non-small cell lung cancer (NSCLC) based on an analytic cost-effectiveness model using published data and modelling assumptions from committee experts. In this study, we aimed to re-run this model using real-world multi-centre UK data., Materials and Methods: Retrospective data was collected on consecutive patients with radically treatable clinical stage II and III lung cancer from eleven acute NHS Trusts during the calendar year 01/01/2018 to 31/12/2018. Following a written application to the NICE lung cancer guideline committee, we were granted access to the NG122 brain imaging economic model for the purpose of updating the input parameters in line with the real-world findings from this study., Results: A total of 444 patients had data for analysis. The combined prevalence of occult brain metastases was 6.2% (10/165) in stage II and 6% (17/283) in stage III, compared to 9.5% and 9.3% used in the NICE economic model. 30% of patients with clinical stage III NSCLC and occult BMs on pre-treatment imaging went onto complete the planned curative intent treatment of extracranial disease, 60% completed SRS to the brain and 30% completed WBRT. This compares to 0%, 10% and 0% in the NICE assumptions. The health economic analysis concluded that brain imaging was no longer cost-effective in stage II disease (ICERs £50,023-£115,785) whilst brain imaging remained cost-effective for stage III patients (ICERs 17,000-£22,173), with MRI being the most cost-effective strategy., Conclusion: This re-running of the NICE health economic model with real-world data strongly supports the NICE guideline recommendation for brain imaging prior to curative-intent treatment in stage III lung cancer but questions the cost-effectiveness of CT brain imaging prior to curative-intent treatment in stage II lung cancer., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RM currently works as Associate Director, Value Access and Devolved Nations, Merck, Sharp and Dohme (UK) Ltd. During the time of this work his role was Technical Adviser, Centre for Guidelines, National Institute for Health and Care Excellence. MSD market treatments for lung cancer but this work was completed entirely while in employment with NICE and there are no obvious COI related to MSD’s activities. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Lung cancer screening with low-dose CT reduces lung cancer mortality, but screening requires equitable uptake from candidates at high risk of lung cancer across ethnic and socioeconomic groups that are under-represented in clinical studies. We aimed to assess the uptake of invitations to a lung health check offering low-dose CT lung cancer screening in an ethnically and socioeconomically diverse cohort at high risk of lung cancer., Methods: In this multicentre, prospective, longitudinal cohort study (SUMMIT), individuals aged 55-77 years with a history of smoking in the past 20 years were identified via National Health Service England primary care records at practices in northeast and north-central London, UK, using electronic searches. Eligible individuals were invited by letter to a lung health check offering lung cancer screening at one of four hospital sites, with non-responders re-invited after 4 months. Individuals were excluded if they had dementia or metastatic cancer, were receiving palliative care or were housebound, or declined research participation. The proportion of individuals invited who responded to the lung health check invitation by telephone was used to measure uptake. We used univariable and multivariable logistic regression analyses to estimate associations between uptake of a lung health check invitation and re-invitation of non-responders, adjusted for sex, age, ethnicity, smoking, and deprivation score. This study was registered prospectively with ClinicalTrials.gov, NCT03934866., Findings: Between March 20 and Dec 12, 2019, the records of 2 333 488 individuals from 251 primary care practices across northeast and north-central London were screened for eligibility; 1 974 919 (84·6%) individuals were outside the eligible age range, 7578 (2·1%) had pre-existing medical conditions, and 11 962 (3·3%) had opted out of particpation in research and thus were not invited. 95 297 individuals were eligible for invitation, of whom 29 545 (31·0%) responded. Due to the COVID-19 pandemic, re-invitation letters were sent to only a subsample of 4594 non-responders, of whom 642 (14·0%) responded. Overall, uptake was lower among men than among women (odds ratio [OR] 0·91 [95% CI 0·88-0·94]; p<0·0001), and higher among older age groups (1·48 [1·42-1·54] among those aged 65-69 years vs those aged 55-59 years; p<0·0001), groups with less deprivation (1·89 [1·76-2·04] for the most vs the least deprived areas; p<0·0001), individuals of Asian ethnicity (1·14 [1·09-1·20] vs White ethnicity; p<0·0001), and individuals who were former smokers (1·89 [1·83-1·95] vs current smokers; p<0·0001). When ethnicity was subdivided into 16 groups, uptake was lower among individuals of other White ethnicity than among those with White British ethnicity (0·86 [0·83-0·90]), whereas uptake was higher among Chinese, Indian, and other Asian ethnicities than among those with White British ethnicity (1·33 [1·13-1·56] for Chinese ethnicity; 1·29 [1·19-1·40] for Indian ethnicity; and 1·19 [1·08-1·31] for other Asian ethnicity)., Interpretation: Inviting eligible adults for lung health checks in areas of socioeconomic and ethnic diversity should achieve favourable participation in lung cancer screening overall, but inequalities by smoking, deprivation, and ethnicity persist. Reminder and re-invitation strategies should be used to increase uptake and the equity of response., Funding: GRAIL., Competing Interests: Declaration of interests JLD, CH, ST, HH, and PV were employed by University College London (UCL) as clinical research fellows through SUMMIT Study funding provided by GRAIL. SMJ has received travel expenses from AstraZeneca, BARD1 Bioscience, Optellum, Jansen, Takeda, Evidera, and Achilles Therapeutics for participation on advisory boards; has received honoraria for lectures from Chiesi; and has received travel expenses from AstraZeneca for a US conference. AH has received one honorarium for an advisory board meeting for GRAIL; has received consulting fees from Evidera (for a GRAIL-initiated project); and has previously owned shares in Illumina. NN has received honoraria for advisory, education, and consultancy work from Amgen, AstraZeneca, Bristol-Meyers Squibb, Guardant Health, Janssen, Lilly & Co, Merck Sharp & Dohme, Olympus, Oncimmune, OncLive, PeerVoice, Pfizer, and Takeda, all outside of the submitted work. AN has received consulting fees from Aidence BV, Faculty Science Limited, and MSD; and has received expenses for travelling to a conference from Takeda. A-MM, JT, LF, VB, KG, FB, CL, TA, JM, AD, and SLQ declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs)., Methods: We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older., Results: In the pooled population (N = 1255), any-grade TRAEs occurred in 78% of the patients, grade 3 or 4 TRAEs in 34%, and discontinuation of any regimen component owing to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3 or 4, 2%) and rash (17%; grade 3 or 4, 3%), respectively. The most common grade 3 or 4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5 of 16). Safety in patients aged 75 years or older (n = 174) was generally similar to the overall population, but discontinuation of any regimen component owing to TRAEs was more common (29%). In patients discontinuing NIVO+IPI owing to TRAEs (n = 225), 3-year overall survival was 50% (95% confidence interval: 42.6-56.0), and 42% (31.2-52.4) of 130 responders remained in response 2 years after discontinuation., Conclusions: First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged 75 years or older. Discontinuation owing to TRAEs did not reduce long-term survival., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: Epidermal growth factor receptor (EGFR) mutations (EGFRm) are common oncogene drivers in non-small cell lung cancer (NSCLC). This real-world study explored treatment patterns and time to receive EGFRm test results in patients with advanced EGFRm NSCLC., Methods: A cross-sectional medical chart review was completed May-August 2020 in Australia, Canada, Germany, Italy, South Korea, Taiwan, UK, and USA. Eligible patients had advanced NSCLC and a positive EGFRm test result January-December 2017. Data were abstracted from NSCLC diagnosis to end of follow-up (31 March 2020) or patient's death whichever occurred earlier. The index date was the date of EGFRm confirmation., Results: 223 physicians provided data for 1,793 patients. Patients' mean age was 64.7 years, 54 % were male, 30.7 % had no history of smoking. Overall, 78 % of EGFRm test results were received ≤ 2 weeks after request (range of median 7-14 days across countries). Median time from advanced NSCLC diagnosis to EGFRm test result was 18 days (median range 10-22 days across countries). Over a third (37 %) of patients received a systemic treatment prior to EGFRm result; chemotherapy (25 %) and EGFR-TKI (15 %) were most commonly prescribed; post-EGFR test-result was EGFR-TKI (68 %); 80 % of patients initiated EGFR-TKI at any time point post-NSCLC diagnosis. Of those receiving a first-line EGFR-TKI post-EGFRm testing, 84 % received a TKI alone, 12 % in combination with chemotherapy, and 3 % with other treatments. Median time from first-line EGFR-TKI initiation post-EGFRm testing to first subsequent treatment was 19.8 months., Conclusion: Over one-fifth of patients wait >14 days for their EGFRm test results, affecting their likelihood of receiving first-line EGFR-TKI with 20 % of patients never receiving EGFR TKI treatment. There was significant inter-country variability in the proportion of patients receiving EGFR TKIs. Our study highlights the need to improve EGFRm testing turnaround times and treatment initiation across countries., Competing Interests: Declaration of Competing Interest Janakiraman Subramanian: Advisory board member for AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Eli Lilly, G1 therapeutics, Jazz Pharma, Janssen, Novartis, Pfizer; Takeda; Speaker honorarium from AstraZeneca, G1 therapeutics, Janssen, Jazz Pharma & Boehringer Ingelheim. Natasha Leighl: Honoraria received for CME lectures from Amgen, BMS, GlaxoSmithKline, MSD, Novartis, Puma Biotechnology, Sanofi Genzyme and Takeda; Institutional research funding received from Amgen, Array, AstraZeneca, Bayer, BMS, Eli Lilly, EMD Serono, Guardant Health, Inivata, MSD, Novartis, Pfizer, Roche and Takeda. Yoon-La Choi: No disclosures or potential conflicts of interest. Teh-Ying Chou: No disclosures or potential conflicts of interest. Jeffrey Gregg is an employee of Harbinger Oncology, Cambridge, MA, USA. Rina Hui: Advisory board member for AstraZeneca, BMS, Eisai, Eli Lilly, Merck, MSD, Novartis, OncoSec, Pfizer, Roche, Seagen; Speaker honorarium from AstraZeneca, Eli Lilly, MSD, Novartis. Antonio Marchetti: No disclosures or potential conflicts of interest. Neal Navani is supported by an MRC Clinical Academic Research Partnership (MR/T02481X/1), and has received honoraria or non-financial support for advisory boards or speaker bureau from Amgen, AstraZeneca, Bristol-Meyers Squibb, Guardant, Janssen, Lilly & Co, Merck Sharp and Dohme, Olympus, Oncimmune, OncLive, PeerVoice, Pfizer and Takeda, outside of the submitted work. Maiyan Chau and Aliki Taylor are employees of AstraZeneca, Cambridge, UK; Maiyan Chau owns stock and stock options in AstraZeneca. Doreen A Kahangire is a Consultant of AZ Cambridge, UK and does not own or hold stock options. Tom Bailey, Mark Silvey, Rebecca Makin, and Liane Gillespie‑Akar are employees of Adelphi Real World, Bollington, Cheshire, UK., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Large lung nodules (≥15 mm) have the highest risk of malignancy, and may exhibit important differences in phenotypic or clinical characteristics to their smaller counterparts. Existing risk models do not stratify large nodules well. We aimed to develop and validate an integrated segmentation and classification pipeline, incorporating deep-learning and traditional radiomics, to classify large lung nodules according to cancer risk., Methods: 502 patients from five U.K. centres were recruited to the large-nodule arm of the retrospective LIBRA study between July 2020 and April 2022. 838 CT scans were used for model development, split into training and test sets (70% and 30% respectively). An nnUNet model was trained to automate lung nodule segmentation. A radiomics signature was developed to classify nodules according to malignancy risk. Performance of the radiomics model, termed the large-nodule radiomics predictive vector (LN-RPV), was compared to three radiologists and the Brock and Herder scores., Findings: 499 patients had technically evaluable scans (mean age 69 ± 11, 257 men, 242 women). In the test set of 252 scans, the nnUNet achieved a DICE score of 0.86, and the LN-RPV achieved an AUC of 0.83 (95% CI 0.77-0.88) for malignancy classification. Performance was higher than the median radiologist (AUC 0.75 [95% CI 0.70-0.81], DeLong p = 0.03). LN-RPV was robust to auto-segmentation (ICC 0.94). For baseline solid nodules in the test set (117 patients), LN-RPV had an AUC of 0.87 (95% CI 0.80-0.93) compared to 0.67 (95% CI 0.55-0.76, DeLong p = 0.002) for the Brock score and 0.83 (95% CI 0.75-0.90, DeLong p = 0.4) for the Herder score. In the international external test set (n = 151), LN-RPV maintained an AUC of 0.75 (95% CI 0.63-0.85). 18 out of 22 (82%) malignant nodules in the Herder 10-70% category in the test set were identified as high risk by the decision-support tool, and may have been referred for earlier intervention., Interpretation: The model accurately segments and classifies large lung nodules, and may improve upon existing clinical models., Funding: This project represents independent research funded by: 1) Royal Marsden Partners Cancer Alliance, 2) the Royal Marsden Cancer Charity, 3) the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, 4) the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College London, 5) Cancer Research UK (C309/A31316)., Competing Interests: Declaration of interests Dr Navani is supported by a Medical Research Council Clinical Academic Research Partnership (MR/T02481X/1). This work was partly undertaken at the University College London Hospitals/University College London that received a proportion of funding from the Department of Health’s National Institute for Health Research (NIHR) Biomedical Research Centre’s funding scheme (NN). Dr Navani reports honoraria for educational talks or advisory boards from Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Guardant Health, Janssen, Lilly, Merck Sharp & Dohme, Olympus, OncLive, PeerVoice, Pfizer, and Takeda. Dr Nair receives research grants from the Department of Health’s NIHR Biomedical Research Centre and GRAIL. He has received consulting fees from Aidence BV, Faculty Science Limited and MSD. He has received a travel bursary from Takeda. He participates on advisory boards for Aidence BV and Faculty Science Limited. He has leadership roles within the British Society of Thoracic Imaging, the British Lung Foundation and the NHS England Targeted Lung Health Checks Programme. Dr Lee is funded by the Royal Marsden NIHR BRC, and Royal Marsden Cancer charity. RL's institution receives compensation for time spent in a secondment role for the lung health check program and as a National Specialty Lead for the National Institute of Health and Care Research. He has received research funding from CRUK, Innovate UK (co-funded by GE Healthcare, Roche and Optellum), SBRI (co-applicant in grants with QURE.AI), RM Partners Cancer Alliance and NIHR (co-applicant in grants with Optellum). He has received honoraria from CRUK. Professor Devaraj is employed by and has stocks in Brainomix. He receives consulting fees from Roche and Boehringer Ingelheim. The other authors report no potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Patient-derived xenograft (PDX) models are an effective preclinical in vivo platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathologic features, mutational profiles, gene expression, and copy-number aberrations. Most of the PDXs are models of non-small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine carcinomas, two adenosquamous carcinomas, and one pleomorphic carcinoma. Models with both de novo and acquired resistance to targeted therapies with tyrosine kinase inhibitors are available in the collection. The genomic profiles of the LUAD and LUSC PDX models are consistent with those observed in patient tumors from The Cancer Genome Atlas and previously characterized gene expression-based molecular subtypes. Clinically relevant mutations identified in the original patient tumors were confirmed in engrafted PDX tumors. Treatment studies performed in a subset of the models recapitulated the responses expected on the basis of the observed genomic profiles. These models therefore serve as a valuable preclinical platform for translational cancer research., Significance: Patient-derived xenografts of lung cancer retain key features observed in the originating patient tumors and show expected responses to treatment with standard-of-care agents, providing experimentally tractable and reproducible models for preclinical investigations., (©2022 The Authors; Published by the American Association for Cancer Research.)

Lung cancer screening (LCS) eligibility is largely determined by tobacco consumption. Primary care smoking data could guide LCS invitation and eligibility assessment. We present observational data from the SUMMIT Study, where individual self-reported smoking status was concordant with primary care records in 75.3%. However, 10.3% demonstrated inconsistencies between historic and most recent smoking status documentation. Quantified tobacco consumption was frequently missing, precluding direct LCS eligibility assessment. Primary care recorded "ever-smoker" status, encompassing both recent and historic documentation, can be used to target LCS invitation. Identifying those with missing or erroneous "never-smoker" smoking status is crucial for equitable invitation to LCS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Eligibility for lung cancer screening (LCS) requires assessment of lung cancer risk, based on smoking history alongside demographic and medical factors. Reliance on individual face-to-face eligibility assessment risks inefficiency and costliness. The SUMMIT Study introduced a telephone-based lung cancer risk assessment to guide invitation to face-to-face LCS eligibility assessment, which significantly increased the proportion of face-to-face attendees eligible for LCS. However, levels of agreement between phone screener and in-person responses were lower in younger individuals and minority ethnic groups. Telephone-based risk assessment is an efficient way to optimise selection for LCS appointments but requires further iteration to ensure an equitable approach., Competing Interests: Competing interests: JLD, CH, ST, HH, PV, JM, AH and SMJ are investigators for the SUMMIT Study within which the present study cohort is embedded. SUMMIT is sponsored and conducted by University College London and funded by GRAIL LLC. through a research grant awarded to SMJ as principal investigator. SLQ collaborates on the SUMMIT study and has received honorarium from Elsevier for writing a book chapter. AN is a member of the advisory board for Aidence BV. AH has received an honorarium for an advisory board meeting for GRAIL, a consultation fee for Evidera Inc for a GRAIL initiated project, and previously owned shares in Illumina. SMJ has received honoraria from Astra Zeneca, BARD1 Bioscience and Jansen for being an Advisory Board Expert and travel to a US conference. SMJ received grant funding from Owlstone for a separate research study and has a family member who is an employee of Astra Zeneca. SMJ has received travel funding for a conference from Takeda and an honorarium for planning and speaking at educational meetings from Astra Zeneca. All authors perceive that these disclosures pose no academic conflict for this study and declare no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Successful lung cancer screening delivery requires sensitive, timely reporting of low-dose computed tomography (LDCT) scans, placing a demand on radiology resources. Trained non-radiologist readers and computer-assisted detection (CADe) software may offer strategies to optimise the use of radiology resources without loss of sensitivity. This report examines the accuracy of trained reporting radiographers using CADe support to report LDCT scans performed as part of the Lung Screen Uptake Trial (LSUT)., Methods: In this observational cohort study, two radiographers independently read all LDCT performed within LSUT and reported on the presence of clinically significant nodules and common incidental findings (IFs), including recommendations for management. Reports were compared against a 'reference standard' (RS) derived from nodules identified by study radiologists without CADe, plus consensus radiologist review of any additional nodules identified by the radiographers., Results: A total of 716 scans were included, 158 of which had one or more clinically significant pulmonary nodules as per our RS. Radiographer sensitivity against the RS was 68-73.7%, with specificity of 92.1-92.7%. Sensitivity for detection of proven cancers diagnosed from the baseline scan was 83.3-100%. The spectrum of IFs exceeded what could reasonably be covered in radiographer training., Conclusion: Our findings highlight the complexity of LDCT reporting requirements, including the limitations of CADe and the breadth of IFs. We are unable to recommend CADe-supported radiographers as a sole reader of LDCT scans, but propose potential avenues for further research including initial triage of abnormal LDCT or reporting of follow-up surveillance scans., Key Points: • Successful roll-out of mass screening programmes for lung cancer depends on timely, accurate CT scan reporting, placing a demand on existing radiology resources. • This observational cohort study examines the accuracy of trained radiographers using computer-assisted detection (CADe) software to report lung cancer screening CT scans, as a potential means of supporting reporting workflows in LCS programmes. • CADe-supported radiographers were less sensitive than radiologists at identifying clinically significant pulmonary nodules, but had a low false-positive rate and good sensitivity for detection of confirmed cancers., (© 2022. The Author(s).)

Targeted therapy against actionable variants has revolutionised the treatment landscape for non-small cell lung cancer (NSCLC). Approximately half of NSCLC adenocarcinomas have an actionable variant, making molecular testing a critical component of the diagnostic process to personalise therapeutic options, optimise clinical outcomes and minimise toxicity. Recently, genomic testing in England has undergone major changes with the introduction of Genomic Laboratory Hubs, designed to consolidate and enhance existing laboratory provision and deliver genomic testing as outlined in the National Genomic Test Directory. Similar changes are ongoing in Scotland, Wales and Northern Ireland. However, multiple challenges exist with current tissue acquisition procedures and the molecular testing pathway in the UK, including quantity and quality of available tissue, adequacy rates, test availability among genomic laboratories, turnaround times, multidisciplinary team communication, and limited guidance and standardisation. The COVID-19 pandemic has added an extra layer of complexity. Herein, we summarise best practice recommendations, based on expert opinion, to overcome existing challenges in the UK. The least invasive biopsy technique should be undertaken with the aim of acquiring the greatest quality and quantity of tissue. Use of sedation should be considered to improve patient experience. Rapid on-site evaluation may also be useful to help guide adequate sampling, and liquid biopsy may be beneficial in some instances. Sample processing should be appropriate to facilitate biomarker testing, in particular, next-generation sequencing for comprehensive genomic information. Steps to optimise tissue utilisation and turnaround times, such as planning of tissue usage, limiting immunohistochemistry, tumour enrichment, and reflex testing at diagnosis, should be implemented. Guidelines for tissue acquisition and sample processing may help to improve sample adequacy to perform downstream testing. Communication among genomic laboratories will help to standardise test availability across England and local auditing could identify further areas for optimisation, including ways to improve turnaround times and adequacy rates., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Pathologists have routinely observed distinct histologic patterns of growth in early-stage lung adenocarcinoma (LUAD), which have been suggested to be associated with prognosis. Herein, we investigated the relationship between LUAD patterns of growth, as defined by the updated international association for the study of lung cancer (IASLC) grading criteria, and differences in the tumor immune microenvironment to identify predictors of response to immunotherapy., Methods: 174 resected stage I-III LUAD tumors were classified by histologic pattern of growth (i.e. solid, micropapillary, acinar, papillary, and lepidic) and then grouped as well differentiated, moderately differentiated, and poorly differentiated. Comprehensive multiplatform analysis including whole exome sequencing, gene expression profiling, immunohistochemistry, CIBERSORT, and T-cell receptor sequencing was performed and groups were compared for differences in genomic drivers, immune cell infiltrate, clonality, and survival. Finally, multivariate analysis was performed adjusting for pathologic stage and smoking status., Results: Poorly differentiated tumors demonstrated a strong association with smoking relative to moderately differentiated or well differentiated tumors. However, unlike in prior reports, poorly differentiated tumors were not associated with a worse survival after curative-intent resection. Genomic analysis revealed that poorly differentiated tumors are associated with high tumor mutation burden but showed no association with oncogenic drivers. Immune analyses revealed that poorly differentiated tumors are associated with increased T-cell clonality, expression of PD-L1, and infiltration by cytotoxic CD8 T-cells, activated CD4 T-cells, and pro-inflammatory (M1) macrophages. Finally, multivariate analysis controlling for stage and smoking status confirmed independence of immune differences between IASLC grade groups., Conclusions: Poorly differentiated tumors, as defined by the updated IASLC grading criteria, are associated with a distinct immunogenic tumor microenvironment that predicts for therapeutic response to immune agents, including checkpoint inhibitors, and should be included in the clinical trial design of immunotherapy studies in early-stage lung adenocarcinoma., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexandre Reuben serves on the Scientific Advisory Board and has received honoraria from Adaptive Biotechnologies. John V. Heymach serves on the Scientific Advisory Committees of AstraZeneca, EMD Serono, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Eli Lilly, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Roche, Leads Biolabs, and RefleXion and provides research support to AstraZeneca, Bristol-Myers Squibb, and Spectrum and has received royalties and licensing fees from Spectrum. All other authors declare no potential conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: National targets for timely diagnosis and management of a potential cancer are driven in part by the perceived risk of disease progression during avoidable delays. However, it is unclear to what extent time-to-treatment impacts prognosis for patients with non-small cell lung cancer, with previous reviews reporting mixed or apparently paradoxical associations. This systematic review focuses on potential confounders in order to identify particular patient groups which may benefit most from timely delivery of care., Methods: Medline, EMBASE and Cochrane databases were searched for publications between January 2012 and October 2020, correlating timeliness in secondary care pathways to patient outcomes. The protocol is registered with PROSPERO (the International Prospective Register of Systematic Reviews; ID 99239). Prespecified factors (demographics, performance status, histology, stage and treatment) are examined through narrative synthesis., Results: Thirty-seven articles were included. All but two were observational. Timely care was generally associated with a worse prognosis in those with advanced stage disease (6/8 studies) but with better outcomes for patients with early-stage disease treated surgically (9/12 studies). In one study, patients with squamous cell carcinoma referred for stereotactic ablative radiotherapy benefited more from timely care, compared with patients with adenocarcinoma. One randomised controlled trial supported timeliness as being advantageous in those with stage I-IIIA disease., Conclusion: There are limitations to the available evidence, but observed trends suggest timeliness to be of particular importance in surgical candidates. In more advanced disease, survival trends are likely outweighed by symptom burden, performance status or clinical urgency dictating timeliness of treatment., Competing Interests: Competing interests: This project has received funding from a CRUK Early Diagnosis Advisory Group (EDAG) project award, C11558/A25623. SG is supported by funding from CRUK project award C11558/A25623. TR is funded by a National Institute for Health Research (NIHR) Doctoral Research Fellowship (ref: DRF-2016-09-054), and was previously supported by a Royal Marsden Partners (RMP) Research Fellowship. NN is supported by an MRC Clinical Academic Research Partnership (MR/T02481X/1). SMJ and HH are supported by a grant from GRAIL Inc for work on the SUMMIT study. SMJ has received funding from Jansen and fees from Bard1, Takeda and Astra Zeneca, outside of the submitted work. MDP has received lecture fees for Astra Zeneca, outside of the submitted work. NN has received fees or non-financial support from Amgen, Astra Zeneca, Bristol-Meyers Squibb, Lilly & Co, Merck Sharp and Dohme, Olympus, Oncimmune, OncLive, PeerVoice, Pfizer and Takeda, outside of the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Previous studies regarding the prevalence of frailty in patients with lung cancer and mortality in frail patients with lung cancer are inconsistent and require clarification., Research Question: What is the prevalence and impact of frailty in patients with lung cancer?, Study Design and Methods: This systematic review and meta-analysis used a combination of free-text terms and medical subject headings terms, according to the database requirements in MEDLINE/PubMed, Scopus, and Cochrane Library from inception until November 15, 2020., Results: A total of 2,571 articles were identified, and 16 articles involving 4,183 patients were included for study. The prevalence of frailty in lung cancer was 45% (95% CI, 28-61; I 2  = 99.5%; P < .0001). In patients with lung cancer, frailty was associated with an increased hazard ratio for mortality (hazard ratio, 3.01; 95% CI, 1.77-5.10; P < .001)., Interpretation: The prevalence of frailty in lung cancer is 45%, which has a significant negative impact on survival of patients with lung cancer. These results highlight the importance of measuring frailty, which provides important prognostic information, and may provide opportunities for interventions to improve outcomes in patients with lung cancer., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: Advances in biological measurement technologies are enabling large-scale studies of patient cohorts across multiple omics platforms. Holistic analysis of these data can generate actionable insights for translational research and necessitate new approaches for data integration and mining., Methods: We present a novel approach for integrating data across platforms on the basis of the shared nearest neighbors algorithm and use it to create a network of multiplatform data from the immunogenomic profiling of non-small-cell lung cancer project., Results: Benchmarking demonstrates that the shared nearest neighbors-based network approach outperforms a traditional gene-gene network in capturing established interactions while providing new ones on the basis of the interplay between measurements from different platforms. When used to examine patient characteristics of interest, our approach provided signatures associated with and new leads related to recurrence and TP53 oncogenotype., Conclusion: The network developed offers an unprecedented, holistic view into immunogenomic profiling of non-small-cell lung cancer, which can be explored through the accompanying interactive browser that we built., Competing Interests: Alexandre ReubenHonoraria: Adaptive BiotechnologiesConsulting or Advisory Role: Adaptive Biotechnologies Natalie VokesHonoraria: SanofiConsulting or Advisory Role: Sanofi/Regeneron, OncoCyte, LillyResearch Funding: OncoCyte Junya FujimotoConsulting or Advisory Role: Sakura Finetek Japan, ReasonWhy Lauren A. ByersHonoraria: UpToDate, Clinical Care OptionsConsulting or Advisory Role: Merck Sharp & Dohme Corp, Arrowhead Pharmaceuticals, Chugai Pharma, AstraZeneca, Genetech Inc, AbbVie, BeiGene, Jazz PharmaceuticalsResearch Funding: AstraZeneca (Inst), Amgen (Inst), Jazz Pharmaceuticals (Inst)Patents, Royalties, Other Intellectual Property: Pending patents on biomarkers for lung cancer (eg, methods of selection of patients for treatment and novel biomarker tests)—recipient would be my institution and self Lorenzo FedericoResearch Funding: Obsidian Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: Charles River Laboratories. Agreement for the commercialization of transplantable tumor lines Marie-Andree ForgetConsulting or Advisory Role: Proteios TechnologyPatents, Royalties, Other Intellectual Property: License to Obsidian Therapeutics Daniel J. McGrailPatents, Royalties, Other Intellectual Property: Pending patents on biomarkers for sensitivity to cancer therapeutics Younghee LeeEmployment: MD Anderson Cancer Center Jeffrey J. KovacsEmployment: Aktis OncologyStock and Other Ownership Interests: Aktis OncologyPatents, Royalties, Other Intellectual Property: I was the recipient of a royalty payment from an agreement between Ipsen and the MD Anderson Cancer Center pertaining to the licensing and development of IACS-6274/IPN60090 Ignacio I. WistubaConsulting or Advisory Role: Genentech/Roche, Bristol Myers Squibb, HTG Molecular Diagnostics, Asuragen, Pfizer, AstraZeneca/MedImmune, GlaxoSmithKline, Guardant Health, Merck, MSD Oncology, Bayer, OncoCyte, Flame Biosciences, Amgen, Novartis, Daiichi Sankyo/Lilly, Daiichi Sankyo/Astra Zeneca, SanofiSpeakers' Bureau: Pfizer, MSD Oncology, Roche, Merck, AstraZeneca, Daiichi Sankyo/LillyResearch Funding: Genentech (Inst), Merck (Inst), HTG Molecular Diagnostics (Inst), Adaptimmune (Inst), EMD Serono (Inst), Pfizer (Inst), MedImmune (Inst), Takeda (Inst), Karus Therapeutics (Inst), Amgen (Inst), 4D Molecular Therapeutics (Inst), Bayer (Inst), Novartis (Inst), Guardant Health (Inst), Adaptive Biotechnologies (Inst), Johnson & Johnson (Inst), Iovance Biotherapeutics (Inst), Akoya Biosciences (Inst), Sanofi (Inst) Andrew FutrealStock and Other Ownership Interests: Scorpion Therapeutics Ara VaporciyanTravel, Accommodations, Expenses: AstraZeneca Boris SepesiConsulting or Advisory Role: Bristol Myers Squibb/Medarex, AstraZeneca, MedscapeSpeakers' Bureau: AstraZeneca, PeerViewTravel, Accommodations, Expenses: PeerView John V. HeymachStock and Other Ownership Interests: Cardinal Spine, Bio-TreeConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, Spectrum Pharmaceuticals, Guardant Health, Hengrui Pharmaceutical, GlaxoSmithKline, EMD Serono, Takeda, Sanofi/Aventis, Genentech/Roche, Boehringer Ingelheim, Mirati Therapeutics, Janssen, Nexus Health Systems, Pneuma Respiratory, Lilly (Inst)Speakers' Bureau: IDEOlogy Health, MJH Life SciencesResearch Funding: AstraZeneca (Inst), Spectrum Pharmaceuticals, GlaxoSmithKlinePatents, Royalties, Other Intellectual Property: Licensing agreement between Spectrum and MD Anderson (including myself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations Chantale BernatchezEmployment: Cell Therapy Manufacturing CenterStock and Other Ownership Interests: Myst TherapeuticsConsulting or Advisory Role: Myst TherapeuticsResearch Funding: Iovance Biotherapeutics, Obsidian Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: Patent pending on BTLA as a marker for better CD8 T cells for adoptive immunotherapy, Patent pending—Methods for expansion of Tumor-Infiltrating Lymphocytes and use thereof, Patent pending—Human 4-1BB agonist antibodies and methods of use thereofExpert Testimony: Allogene Therapeutics Cara HaymakerStock and Other Ownership Interests: BriaCellConsulting or Advisory Role: NanobiotixResearch Funding: Idera (Inst), Iovance Biotherapeutics (Inst), Dragonfly Therapeutics (Inst), Sanofi (Inst), BTG (Inst)Patents, Royalties, Other Intellectual Property: Patent Appl No. 62/977, 672 (Inst) Tina CasconeHonoraria: Society for Immunotherapy of Cancer, Roche, Bristol Myers Squibb, Medscape, PeerViewConsulting or Advisory Role: MedImmune, Bristol Myers Squibb, Genentech, EMD Serono, AstraZeneca, Merck, Arrowhead PharmaceuticalsResearch Funding: Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), EMD Serono (Inst), MedImmune (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Parker Institute for Cancer Immunotherapy Jianjun ZhangHonoraria: Roche, Sino-USA Biomedical Platform, Geneplus, OrigiMed, Innovent Biologics, CancerNet, Zhejiang Cancer Hospital, Innovent Biologics, Zhejiang Cancer Hospital, Suzhou Medical Association, Hengrui MedicineConsulting or Advisory Role: AstraZeneca, Geneplus, Capital Medical University, Johnson & Johnson/Janssen, Novartis, Hunan Cancer HospitalResearch Funding: Merck, NovartisTravel, Accommodations, Expenses: Innovent Biologics, Zhejiang Cancer Hospital Timothy P. HeffernanStock and Other Ownership Interests: Cullgen, Roivant DiscoveryConsulting or Advisory Role: Cullgen, Roivant Discovery, Silicon TherapeuticsResearch Funding: Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Blueprint Medicines (Inst), Schrodinger (Inst)Patents, Royalties, Other Intellectual Property: I am a coinventor on material and method of use patents for therapeutics developed within MD Anderson. I may personally benefit from milestone and royalty agreements through MDA alliances and out-license agreementsTravel, Accommodations, Expenses: Cullgen, Roivant Marcelo V. NegraoConsulting or Advisory Role: Mirati Therapeutics, MerckResearch Funding: Mirati Therapeutics, AstraZeneca, Novartis, Pfizer, ZIOPHARM Oncology, Checkmate Pharmaceuticals, Genentech, Alaunos TherapeuticsOther Relationship: ZIOPHARM Oncology, Apothecom, Ashfield Healthcare Don L. GibbonsStock and Other Ownership Interests: Exact Sciences, NektarConsulting or Advisory Role: Sanofi, GlaxoSmithKline, Janssen Research & Development, Ribon Therapeutics, Mitobridge, Lilly, Menarini, Napa TherapeuticsResearch Funding: Janssen Research & Development, Takeda, AstraZeneca, Mitobridge, Ribon Therapeutics, Boehringer Ingelheim (Inst), Mirati Therapeutics (Inst), NGM BiopharmaceuticalsTravel, Accommodations, Expenses: AstraZeneca/MedImmune, BerGenBio, TakedaNo other potential conflicts of interest were reported.

Accurately explaining perioperative mortality and risk to patients is an essential part of shared decision making. In the case of lung cancer surgery, the currently available multivariable mortality prediction tools perform poorly, and could mislead patients. Using data from 2004 to 2012, this group has previously produced data tables for 90-day postoperative mortality, to be used as a communication aid in the consenting process. Using National Lung Cancer Clinical Outcomes audit data from 2017 to 2018, we have produced updated early mortality tables, to reflect current thoracic surgery practice., Competing Interests: Competing interests: HM has nothing to disclose. DRB reports grants from Cancer Research UK, personal fees from Roche, personal fees from Astra Zeneca, personal fees from MSD, personal fees from BMS, outside the submitted work. RH reports personal fees from Galapagos, outside the submitted work. NN is supported by an MRC Clinical Academic Research Partnership (MR/T02481X/1). NN has received fees or non-financial support fromAmgen, Astra Zeneca, Bristol-Meyers Squibb, Lilly & Co, Merck Sharp and Dohme, Olympus,Oncimmune, OncLive, PeerVoice, Pfizer and Takeda, outside of the submitted work. DWreports grants from Medtronic, personal fees from Astra Zeneca UK, and is a salariedemployee of the NHS England Improvement GIRFT programme. ELO'D has nothing to disclose., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This open-label, phase 1-2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC)., Methods: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data., Results: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses., Conclusions: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Delivering lung cancer care during the COVID-19 pandemic has posed significant and ongoing challenges. There is a lack of published COVID-19 and lung cancer evidence-based reviews, including for the whole patient pathway. We searched for COVID-19 and lung cancer publications and brought together a multidisciplinary group of stakeholders to review and comment on the evidence and challenges. A rapid review of the literature was undertaken up to 28 October 2020, producing 144 papers, with 113 full texts screened. We focused on new primary data collection (qualitative or quantitative evidence) and excluded case reports, editorials and commentaries. Following exclusions, 15 published papers were included in the review and are summarised. They included one qualitative paper and 14 quantitative studies (surveys or cohort studies), with a total of 2295 lung cancer patients data included (mean study size 153 patients; range 7-803). Review of current evidence and commentary included awareness and help-seeking; lung cancer screening; primary care assessment and referral; diagnosis and treatment in secondary care, including oncology and surgery; patient experience and palliative care. Cross-cutting themes and challenges were identified using qualitative methods for patients, healthcare professionals and service delivery, with a clear need for continued studies to guide evidence-based decision-making., (© 2021. The Author(s), under exclusive licence to Cancer Research UK.)

Stereotactic body radiation therapy (SBRT) is an effective and well-tolerated treatment for medically inoperable patients with early stage NSCLC. SBRT is a noninvasive treatment involving the delivery of ablative radiation doses with high precision in the course of a few treatments. Relative to conventionally fractionated radiation, SBRT achieves superior local control and survival. SBRT use has increased dramatically in the past 15 years and is currently considered the standard of care in cases of inoperable early stage NSCLC. It is being increasingly applied to more complex patient populations at higher risk of treatment-related toxicity. In these more complex patients, there is an increasing need to balance patient and treatment factors in selecting the optimal patients for SBRT. Here, we review several challenging clinical scenarios often encountered in thoracic multidisciplinary tumor boards., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Introduction: Optimal treatment for 'potentially resectable' stage III-N2 non-small cell lung cancer (NSCLC) requires multimodality treatment: local treatment (surgery or radiotherapy) and systemic anticancer therapy. There is no clear evidence of superiority for survival between the two approaches and little research has explored quality of life (QOL). This study will inform the design of a phase III randomised trial of surgery versus no surgery as part of multimodality treatment for stage III-N2 NSCLC with QOL as a primary outcome., Methods and Analysis: Patient participants will be randomised to receive multimodality treatment (1) with surgery OR (2) without surgery. The Quintet Recruitment Intervention will be used to maximise recruitment. Eligible patients will have 'potentially resectable' N2 NSCLC and have received a multidisciplinary team recommendation for multimodality treatment. Sixty-six patients and their carers will be recruited from 8 UK centres. Patient/carer QOL questionnaires will be administered at baseline, weeks 6, 9, 12 and month 6. Semistructured interviews will be conducted. Quantitative data will be analysed descriptively and qualitative data will be analysed using framework analysis., Ethics and Dissemination: Ethical approval has been obtained. Results will be disseminated via publications, national bodies and networks, and patient and public involvement groups., Trial Registration: NCT04540757., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Historically, patients with stage IV non-small cell lung cancer (NSCLC) have been treated with chemotherapy alone, reserving local therapies for symptom palliation. However, evidence has accumulated that a subset of patients with oligometastatic NSCLC (OM-NSCLC) may benefit from local ablative therapies (LATs). In this article, we review the data that have formed the rationale for LAT, specifically radiotherapy, and the prospective trials that support its use in this population. Finally, we examine the evolving role of LAT in patients with OM-NSCLC in the context of immunotherapy and targeted therapies, as well as discuss ongoing clinical trials incorporating LAT in these patients.

Purpose: To determine if Medicaid expansion is associated with increased volumes of lung cancer screenings., Methods: A quasi-experimental study was performed to compare the annual growth rates in lung cancer screenings between states that expanded Medicaid (n = 31) versus those that did not (n = 17). Using the American College of Radiology Lung Cancer Screening Registry, we calculated the average annual growth rate between 2016 and 2019 for both groups. Secondary analyses between these two groups also included calculations of the percentages of studies considered appropriate by USPSTF criteria., Results: No significant difference was identified in the average annual growth in lung cancer screenings between Medicaid expanding and non-expanding states (57.6%, 50.3%, P = 0.51). No difference was observed in the percentage of studies considered appropriate (Medicaid expanding = 89.6%, non-expanding = 90.2%, P = 0.72). At baseline, there were socioeconomic differences between both groups of states. Medicaid expanding states had a more urban population (76.5% versus 67.9%, P = 0.05) and higher average incomes ($56,947, $49,876, P < 0.05)., Conclusion: No association is found between Medicaid expansion and increasing volumes of lung cancer screening exams. Although no data is available in the registry for screening exams before the implementation of Medicaid expansion (2014), most nationwide estimates of lung screening rates report a low baseline (<5%). Furthermore, despite being advantaged in other ways, such as with a more urban population or with higher incomes, the Medicaid expansion cohort does not demonstrate a higher growth rate. These findings suggest Medicaid expansion alone will not increase lung cancer screenings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC., Methods: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested., Results: Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; P = .37; median, 9.2 v 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%)., Conclusion: Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals., Competing Interests: Taofeek K. OwonikokoStock and Other Ownership Interests: Cambium Medical TechnologiesConsulting or Advisory Role: Novartis, Celgene, Lilly, Sandoz, Abbvie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol-Myers Squibb, MedImmune, BerGenBio, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Heron Pharmaceutical, ARMO BioSciences, MerckSpeakers' Bureau: AbbvieResearch Funding: Novartis, Astellas Pharma, Celgene, Bayer, Stem CentRx, Regeneron, AstraZeneca/MedImmune, Abbvie, G1 Therapeutics, Bristol-Myers Squibb, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, MerckPatents, Royalties, Other Intellectual Property: Overcoming acquired resistance to chemotherapy treatments through suppression of STAT3, Selective chemotherapy treatments and diagnostic methods related thereto, DR4 modulation and its implications in EGFR-target cancer therapy ref:18089 PROV (CSP) United States patent application no. 62/670,210 June 26, 2018 (Co-Inventor), Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor)Other Relationship: Roche/Genentech, EMD SeronoUncompensated Relationships: Reflexion Medical Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Blueprint Medicines, Amgen, Merck KGaA, LOXO, Abbvie, Daiichi Sankyo, Boehringer Ingelheim, JNJ, Eisai, Puma BiotechnologySpeakers' Bureau: Boehringer Ingelheim, AZDResearch Funding: AstraZeneca, MSD Oncology Ramaswamy GovindanHonoraria: Genentech/Abbvie, Abbvie, GeneplusConsulting or Advisory Role: GlaxoSmithKline, Genentech/Roche, Abbvie, Celgene, AstraZeneca/MedImmune, Merck Serono, Pfizer, Bristol-Myers Squibb, EMD Serono, Lilly, Ignyta, Nektar, Phillips Gilmore Oncology, Jounce Therapeutics, Roche, Janssen, Amgen, Achilles Therapeutics Neal ReadyConsulting or Advisory Role: Bristol-Myers Squibb, Novartis, Merck, Abbvie, Celgene, Merck Serono, AstraZeneca, G1 Therapeutics, Jazz Pharmaceuticals, RemeronSpeakers' Bureau: Bristol-Myers SquibbResearch Funding: Bristol-Myers Squibb, Merck Martin ReckConsulting or Advisory Role: Lilly, MSD Oncology, Merck Serono, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, Abbvie, Amgen, Mirati Therapeutics, Samsung BioepisSpeakers' Bureau: Roche/Genentech, Lilly, MSD Oncology, Merck Serono, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics Solange PetersHonoraria: Roche, Bristol-Myers Squibb, Novartis, Pfizer, MSD, AstraZeneca, Takeda, IlluminaConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol-Myers Squibb, Pfizer, MSD, Amgen, AstraZeneca, Janssen, Regeneron, Merck Serono, Boehringer Ingelheim, Takeda, Lilly, Abbvie, Bayer, Biocartis, Debiopharm Group, Illumina, PharmaMar, Sanofi, Seattle Genetics, Blueprint Medicines, Daiichi Sankyo, Incyte, Bioinvent, Clovis Oncology, VaccibodyResearch Funding: Roche, Bristol-Myers Squibb, MSD, Amgen, Lilly, AstraZeneca, Pfizer, Illumina, Merck Serono, Novartis, Biodesix, Boehringer Ingelheim, Iovance BiotherapeuticsTravel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, MSD, Sanofi, IncyteUncompensated Relationships: Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals on Oncology associate editor Alejandro NavarroHonoraria: Pfizer, Roche, AstraZenecaConsulting or Advisory Role: Boehringer IngelheimExpert Testimony: Oryzon Genomics, MedsirTravel, Accommodations, Expenses: Boehringer Ingelheim, Pfizer Jerónimo Rodríguez-CidConsulting or Advisory Role: Roche, Bristol-Myers Squibb (Mexico), MSD Oncology, Takeda, BayerSpeakers' Bureau: MSD Oncology, Bristol-Myers Squibb (Mexico), Roche, Boehringer Ingelheim, Novartis, Bayer, Lilly, AstraZenecaResearch Funding: MSD, Bristol-Myers Squibb (Mexico), Roche, Celltrion, Lilly, BeiGene, AstraZenecaTravel, Accommodations, Expenses: Roche, MSD Oncology, AstraZeneca, Boehringer Ingelheim Michael SchenkerResearch Funding: Bristol-Myers Squibb, Roche, Amgen, MSD, Pfizer/EMD Serono, Lilly, Astellas Pharma, AstraZeneca, GlaxoSmithKline, Regeneron, Novartis, Abbvie, Gilead SciencesTravel, Accommodations, Expenses: Bristol-Myers Squibb Jong-Seok LeeConsulting or Advisory Role: AstraZeneca, Ono Pharmaceutical Ivor PercentConsulting or Advisory Role: Bristol-Myers Squibb, Abbvie, Takeda, PharmaMar, Gilead Sciences, G1 TherapeuticsResearch Funding: Heat Biologics, Merck, Celgene, AstraZeneca, Baxter, Incyte, Abbvie, Bristol-Myers Squibb, EpicentRx, Pfizer, Roche, Lilly, Altum Pharmaceuticals, Array BioPharma Carlos H. BarriosStock and Other Ownership Interests: Biomarker, MedSIR, TummiHonoraria: Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Eisai, MSD, Lilly, Bayer, AstraZeneca, Zodiac PharmaConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Novartis, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Libbs, MSD Oncology, United Medical, LillyResearch Funding: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, Abbvie, Astellas Pharma, Biomarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Janssen, Clinica Atlantis, INC Research, Halozyme, Covance, Celgene, inVentiv Health, Merck KGaA, Shanghai Henlius Biotech, Polyphor, PharmaMarTravel, Accommodations, Expenses: Roche/Genentech, Novartis, Pfizer, BMS Brazil, AstraZeneca, MSD Oncology, Lilly Laurent GreillierHonoraria: AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, MSD, Takeda, Abbvie, Novartis, PfizerConsulting or Advisory Role: Roche, Boehringer Ingelheim, Bristol-Myers Squibb, Takeda, MSD, AstraZeneca, Abbvie, NovartisTravel, Accommodations, Expenses: Boehringer Ingelheim, Roche, MSD Sofia BakaConsulting or Advisory Role: MSD Oncology, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, NovartisResearch Funding: Boehringer Ingelheim, Novartis, MSD Oncology, Bristol-Myers Squibb, AstraZeneca, Lilly, Takeda, Genesis PharmaceuticalsTravel, Accommodations, Expenses: Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Demo Pharmaceutical Wen Hong LinEmployment: Bristol-Myers Squibb Giovanni SelvaggiEmployment: Xcovery Holdings IncOther Relationship: Xcovery Holdings Inc Christine BaudeletEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Jonathan BadenEmployment: Bristol-Myers Squibb, Johnson & JohnsonStock and Other Ownership Interests: Bristol-Myers Squibb, Johnson & Johnson Dimple PandyaEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers SquibbPatents, Royalties, Other Intellectual Property: Bristol-Myers Squibb Parul DoshiEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb Hye Ryun KimSpeakers' Bureau: Ono Pharmaceutical, Roche/GenentechNo other potential conflicts of interest were reported.

Radiation therapy is used as a form of treatment for various neoplastic diseases. There are many potential adverse effects of this therapy, including radiation-induced neurotoxicity. Radiation-induced brachial plexopathy (RIBP) may occur due to the fibrosis of neural and perineural soft tissues, leading to ischemic damage of the axons and Schwann cells. The dose of radiation exceeds 55 Gy in many patients who develop symptoms [1]. Current incidence in the United States is 1-2%, and RIBP is most commonly seen in patients who have undergone treatment for breast cancer, lung cancer, or lymphoma [1-3]. Common symptoms include numbness, paresthesia, dysesthesia, and occasional numbness of the arm. Pain is present in the shoulder and proximal arm and is typically mild to moderate in severity. Diagnosis is often made based on clinical presentation and evaluation of imaging to rule out concurrent malignant etiologies of the brachial plexus. Current recommended treatment includes physical therapy and medical management with anticonvulsants, tricyclic antidepressants, and selective serotonin-norepinephrine reuptake inhibitors., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials., Methods: Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m 2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated., Results: After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs., Conclusion: At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.

Non-small cell lung cancer (NSCLC) accounts for approximately one in five cancer-related deaths, and management requires increasingly complex decision making by health care professionals. Many centers have therefore adopted a multidisciplinary approach to patient care, using the expertise of various specialists to provide the best evidence-based, personalized treatment. However, increasingly complex disease staging, as well as expanded biomarker testing and multimodality management algorithms with novel therapeutics, have driven the need for multifaceted, collaborative decision making to optimally guide the overall treatment process. To keep up with the rapidly evolving treatment landscape, national-level guidelines have been introduced to standardize patient pathways and ensure prompt diagnosis and treatment. Such strategies depend on efficient and effective communication between relevant multidisciplinary team members and have both improved adherence to treatment guidelines and extended patient survival. This article highlights the value of a multidisciplinary approach to diagnosis and staging, treatment decision making, and adverse event management in NSCLC. IMPLICATIONS FOR PRACTICE: This review highlights the value of a multidisciplinary approach to the diagnosis and staging of non-small cell lung cancer (NSCLC) and makes practical suggestions as to how multidisciplinary teams (MDTs) can be best deployed at individual stages of the disease to improve patient outcomes and effectively manage common adverse events. The authors discuss how a collaborative approach, appropriately leveraging the diverse expertise of NSCLC MDT members (including specialist radiation and medical oncologists, chest physicians, pathologists, pulmonologists, surgeons, and nursing staff) can continue to ensure optimal per-patient decision making as treatment options become ever more specialized in the era of biomarker-driven therapeutic strategies., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with argininosuccinate synthetase 1 (ASS1)-deficient small-cell lung cancer (SCLC)., Patients and Methods: Patients were enrolled into either a 'sensitive' disease cohort (≥ 90 days response to first-line chemotherapy) or a 'refractory' disease cohort (progression while on chemotherapy or < 90 days afterwards or ≥ third-line treatment). Patients received weekly intramuscular pegargiminase, 320 IU/m 2 (36.8 mg/m 2 ), until unacceptable toxicity or disease progression. The primary endpoint was tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with secondary endpoints including tolerability, pharmacodynamics, and immunogenicity., Results: Between January 2011 and January 2014, 22 patients were enrolled: 9 in the sensitive disease cohort and 13 in the refractory disease cohort. At a pre-planned interim analysis, the best overall response observed was stable disease in 2 patients in each cohort (18.2%). Owing to the lack of response and slow accrual in the sensitive disease cohort, the study was terminated early. Pegargiminase treatment was well-tolerated with no unexpected adverse events or discontinuations., Conclusion: Although pegargiminase monotherapy in SCLC failed to meet its primary endpoint of RECIST-confirmed responses, more recent molecular stratification, including MYC status, may provide new opportunities moving forward., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The Lung Screen Uptake Trial tested a novel invitation strategy to improve uptake and reduce socioeconomic and smoking-related inequalities in lung cancer screening (LCS) participation. It provides one of the first UK-based 'real-world' LCS cohorts. Of 2012 invited, 1058 (52.6%) attended a 'lung health check'. 768/996 (77.1%) in the present analysis underwent a low-dose CT scan. 92 (11.9%) and 33 (4.3%) participants had indeterminate pulmonary nodules requiring 3-month and 12-month surveillance, respectively; 36 lung cancers (4.7%) were diagnosed (median follow-up: 1044 days). 72.2% of lung cancers were stage I/II and 79.4% of non-small cell lung cancer had curative-intent treatment., Competing Interests: Competing interests: SMJ, MR, JLD, CH, ST and HH are supported by funding for a large trial of low dose CT screening, called the ‘SUMMIT Study’ by GRAIL Inc. SLQ and NN collaborate on the SUMMIT Study. SMJ has received honoraria from AstraZeneca, BARD1 Bioscience and Janssen for being an Advisory Board Expert and travel to a US conference. SMJ received grant funding from Owlstone for a separate research study and has a family member who has a financial association with AstraZeneca. MR has received travel funding for a conference from Takeda and an honorarium for planning and speaking at educational meetings from AstraZeneca., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Programmed death-ligand 1 (PD-L1) expression on cancer cells is a clinically important biomarker to select patients with non-small cell lung cancer (NSCLC) for treatment with programmed death-1/PD-L1 inhibitors. Clinical trials of immunotherapy in patients with NSCLC have required histologic evidence for PD-L1 testing; in clinical practice, cytologic samples commonly are acquired in patients with advanced disease., Research Question: This study aims to investigate whether endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples are adequate for PD-L1 testing in NSCLC., Study Design and Methods: This study investigates the sampling adequacy of EBUS-TBNA for PD-L1 testing when compared with other methods. Furthermore, the relationship between clinicopathologic characteristics and PD-L1 expression in the study population have been examined. Five hundred seventy-seven NSCLC specimens were analyzed from consecutive patients with NSCLC across six centers in the United Kingdom and one center in the United States between January 2015 and December 2016., Results: In the EBUS-TBNA group (189 specimens), the overall percentage of patients with successful PD-L1 testing was 94.7%. There was no significant difference in sampling adequacy with other methods of tissue acquisition. Older patients had higher failure rates of PD-L1 testing (OR, 1.06; P = .008). In multivariate analysis, advanced N-stage (P = .048) and presence of brain metastasis (P < .001) were associated with high PD-L1 expression., Interpretation: This large multicenter study shows that EBUS-TBNA provides samples adequate for PD-L1 testing and that advanced N stage and the presence of brain metastasis are associated with high PD-L1 expression., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Interventional pulmonology is a dynamic and evolving field in respiratory medicine. Advances have improved the ability to diagnose and manage diseases of the airways. A shift toward early detection of malignant disease has generated a focus on innovative diagnostic techniques. With patient populations living longer with malignant and benign diseases, the role for interventional bronchoscopy has grown. In cancer groups, novel immunotherapies have improved the prospects of clinical outcomes and reignited a focus on optimizing patient performance status to enable access to anticancer therapy. This review discusses current and emerging diagnostic modalities and therapeutic approaches available to manage airway diseases., Competing Interests: Disclosure Dr S. Shaefi is supported by a Grant for Early Medical/Surgical Specialists’ Transition to Aging Research (GEMSSTAR) award (R03AG060179) from the National Institute on Aging and a Mentored Clinical Scientist Research Career Development Award from the National Institute of General Medical Sciences (K08GM134220). This work was undertaken partly at UCLH/UCL, which received a proportion of funding from the Department of Health NIHR Biomedical Research Centre funding stream. Dr N. Navani is supported by a Medical Research Council fellowship (MR/T02481X/1)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Whole body magnetic resonance imaging (WB-MRI) may be more efficient in staging cancers, but can be harder for patients to tolerate. We examined predictors of patient preference for WB-MRI vs. CT/ PET-CT for staging colorectal or lung cancer., Methods: Patients recruited prospectively to two multicentre trials comparing diagnostic accuracy of WB-MRI with standard staging scans were sent two questionnaires: the first, administered at trial registration, captured demographics, educational level and comorbidities; the second, administered after staging completion, measured emotional distress (GHQ-12), positive mood (PANAS), perceived scan burden, patients' beliefs about WB-MRI, and preference for either WB-MRI or CT (colorectal trial), WB-MRI or PET-CT (lung trial). Preference for WB-MRI or CT/ PET-CT was analysed using logistic regression., Results: Baseline and post-staging questionnaires were completed by 97 and 107 patients, respectively. Overall, 56/107 (52%) preferred WB-MRI over standard scans and were more likely to have no additional comorbidities, higher positive mood, greater awareness of potential benefits of WB-MRI and lower levels of perceived WB-MRI scan burden. In adjusted analyses, only awareness of potential WB-MRI benefits remained a significant predictor (OR: 1.516, 95% CIs 1.006-2.284, P = 0.047). Knowledge that WB-MRI does not use radiation predicted preference (adjusted OR: 3.018, 95% CIs 1.099-8.288, P = 0.032), although only 45/107 (42%) patients were aware of this attribute., Conclusions: A small majority of patients undergoing staging of colorectal or lung cancer prefer WB-MRI to CT/ PET-CT. Raising awareness of the potential benefits of WB-MRI, notably lack of ionizing radiation, could influence preference., (© 2020 The Authors. Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Radiologists.)

Rationale: Individuals eligible for lung cancer screening (LCS) by low-dose computed tomography (LDCT) are also at risk of chronic obstructive pulmonary disease (COPD) due to age and smoking exposure. Whether the LCS episode is useful for early detection of COPD is not well established. Objectives: To explore associations between symptoms, comorbidities, spirometry, and emphysema in participants enrolled in the Lung Screen Uptake Trial. Methods: This cross-sectional study was a prespecified analysis nested within Lung Screen Uptake Trial, which was a randomized study testing the impact of differing invitation materials on attendance of 60- to 75-year-old smokers and ex-smokers to a "lung health check" between November 2015 and July 2017. Participants with a smoking history ≥30 pack-years and who quit ≤15 years ago, or meeting a lung cancer risk of ≥1.51% via the Prostate Lung Colorectal Ovarian model or ≥2.5% via the Liverpool Lung Project model, were offered LDCT. COPD was defined and classified according to the GOLD (Global Initiative for Obstructive Lung Disease) criteria using prebronchodilator spirometry. Analyses included the use of descriptive statistics, chi-square tests to examine group differences, and univariable and multivariable logistic regression to explore associations between symptom prevalence, airflow limitation, and visually graded emphysema. Results: A total of 560 of 986 individuals included in the analysis (57%) had prebronchodilator spirometry consistent with COPD; 67% did not have a prior history of COPD and were termed "undiagnosed." Emphysema prevalence in those with known and "undiagnosed" COPD was 73% and 68%, respectively. A total of 32% of those with "undiagnosed COPD" had no emphysema on LDCT. Inhaler use and symptoms were more common in the "known" than the "undiagnosed" COPD group (63% vs. 33% with persistent cough [ P  < 0.001]; 73% vs. 33% with dyspnea [ P  < 0.001]). Comorbidities were common in all groups. Adjusted odds ratio (aOR) of respiratory symptoms were more significant for airflow obstruction (aOR GOLD 1 and 2, 1.57; confidence interval [CI], 1.14-2.17; aOR GOLD 3 and 4, 4.6; CI, 2.17-9.77) than emphysema (aOR mild, 1.12; CI, 0.81-1.55; aOR moderate, 1.33; CI, 0.85-2.09; aOR severe, 4.00; CI, 1.57-10.2). Conclusions: There is high burden of "undiagnosed COPD" and emphysema in LCS participants. Adding spirometry findings to the LDCT enhances identification of individuals with COPD.Clinical trial registered with www.clinicaltrials.gov (NCT02558101).

Amplification of and oncogenic mutations in ERBB2 , the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2 -amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2 . This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy. See related commentary by Rolfo and Russo, p. 643 . This article is highlighted in the In This Issue feature, p. 627 ., (©2020 American Association for Cancer Research.)

Rationale: Low uptake of low-dose computed tomography (LDCT) lung cancer screening, particularly by current smokers of a low socioeconomic position, compromises effectiveness and equity. Objectives: To compare the effect of a targeted, low-burden, and stepped invitation strategy versus control on uptake of hospital-based Lung Health Check appointments offering LDCT screening. Methods: In a two-arm, blinded, between-subjects, randomized controlled trial, 2,012 participants were selected from 16 primary care practices using these criteria: 1 ) aged 60 to 75 years, 2 ) recorded as a current smoker within the last 7 years, and 3 ) no prespecified exclusion criteria contraindicating LDCT screening. Both groups received a stepped sequence of preinvitation, invitation, and reminder letters from their primary care practitioner offering prescheduled appointments. The key manipulation was the accompanying leaflet. The intervention group's leaflet targeted psychological barriers and provided low-burden information, mimicking the concept of the U.K. Ministry of Transport's annual vehicle test ("M.O.T. For Your Lungs"). Measurements and Main Results: Uptake was 52.6%, with no difference between intervention (52.3%) and control (52.9%) groups in unadjusted (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.82-1.16) or adjusted (OR, 0.98; 95% CI, 0.82-1.17) analyses. Current smokers were less likely to attend (adjusted OR, 0.70; 95% CI, 0.56-0.86) than former smokers. Socioeconomic deprivation was significantly associated with lower uptake for the control group only ( P  < 0.01). Conclusions: The intervention did not improve uptake. Regardless of trial arm, uptake was considerably higher than previous clinical and real-world studies, particularly given that the samples were predominantly lower socioeconomic position smokers. Strategies common to both groups, including a Lung Health Check approach, could represent a minimum standard.Clinical trial registered with www.clinicaltrials.gov (NCT02558101) and registered prospectively with the International Standard Registered Clinical/Social Study (N21774741).

Background: Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~ 30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy., Methods: Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14 C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis., Results: A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50 > 2.5 μM at 48 h and 0.1 μM at 72 h) compared with parental PC-9 (IC50: 0.75 μM at 48 h and 0.027 μM at 72 h). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither a T790M mutation nor amplifications of MET and HER2 compared with parental PC-9., Conclusion: Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)